tbuckley/cabot-search huggingface dataset:
P1164: IMAGE-BASED DETECTION OF HIGH-GRADE B CELL LYMPHOMAS (DH-L)
Authors: I. Avivi, C. Perry, O. Ahron, N. Hershkovitz, D. Hershkovitz, A. Avinoam, I. Gazy, N. Paz-Yaacov
Journal: HemaSphere (2022)

Background: Aggressive B cell Non-Hodgkin Lymphomas (B-NHL) are divided into two main categories: diffuse large B cell lymphoma (DLBCL) accounting for 90% of cases, and high-grade B-cell lymphoma (HGBL). Diagnosis of high-grade lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit lymphoma-DHL) is confirmed by fluorescence in situ hybridization (FISH) analysis, demonstrating c-MYC-rearrangement in combination with BCL-2 / BCL-6 rearrangement in lymphoma cells. Accurate and rapid diagnosis of DHL is obligatory, when considering more aggressive treatment regimens (other than R-CHOP), suggested in these patients. Aims: To establish a novel tool for diagnosing DLBCL and DHL, directly on the scanned Hematoxylin and Eosin (H&E) biopsy slides, by applying digital imaging technologies supported by machine learning algorithms. Methods: H&E whole slide images, prepared from biopsies obtained mainly from lymph nodes, but also from extra-nodal organs of patients with aggressive B cell lymphoma histology, were collected from the pathology department at Tel-Aviv Medical center (TASMC). Cases were randomly divided into a training (n=43) and a validation (n=35) set. On-the-fly augmentation was applied to images, together with advanced Convolutional Neural Network (CNN) analysis, to generate the aggressive B-NHL classifier (powered by Imagene-AI). Proprietary multiple instance learning (MIL) algorithms and training scheme, based on cases ranking, rather than absolute values, were applied. The classifier was validated through a testing set in a blinded study scheme, and results were compared to the FISH results for c-MYC and BCL2/6 rearrangements (Figure 1A). Results: The classifier training set was composed of 36 DLBCL NOS and 7 DHL cases. The aggressive B-NHL classifier was validated on a cohort of 35 cases, including 14 DHL cases (diagnosed by FISH) and 21 DLBCL cases. The model demonstrated 100% sensitivity and 90.48% specificity, with an accuracy rate of 94.29% and Area Under the Curve (AUC) of 0.99 (Figure 1B). Two cases were concluded as false positive, including one case that demonstrated rearrangements in substantial percentages of cells, just below the required positivity threshold. Image:Summary/Conclusion: Herein, we demonstrate for the first time a machine learning-based genomic testing solution for the detection and classification of aggressive B-NHL, based on H&E stained slide images. Implementation of this solution in clinical practice can support the diagnosis of DHL, which currently has both technical and financial challenges. Applying the proposed accessible and standardized AI-based method, can improve and facilitate the diagnosis of DHL, thereby directly improving patient care.
Patient-Reported Outcome Measures for Health-Related Quality of Life in Patients With Acne Vulgaris
Authors: Zachary H. Hopkins, Diane Thiboutot, Haya A. Homsi, Lourdes Maria Perez-Chada, John S. Barbieri
Journal: JAMA Dermatology (2022)

Importance Multiple patient-reported outcome measures (PROMs) for health-related quality of life (HRQoL) exist for patients with acne. However, little is known about the content validity and other measurement properties of these PROMs. Objective To systematically review PROMs for HRQoL in adults or adolescents with acne. Data Sources Eligible studies were extracted from PubMed and Embase (OVID). Study Selection Full-text articles published in English or Spanish on development, pilot, or validation studies for acne-specific, dermatology-specific, or generic HRQoL PROMs were included. Development studies included original development studies, even if not studied in acne patients per Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) recommendations. If a study included several diagnoses, the majority (ie, over 50%) of patients must have acne or acne-specific subgroup analyses must be available. Abstract and full-text screening was performed by 2 independent reviewers. Data Extraction and Synthesis Two independent reviewers assessed study quality applying the COSMIN checklist and extracted and analyzed the data. For each distinctive PROM, quality of evidence was graded by measurement property. Main Outcomes and Measures PROM properties (target population, domains, recall period, development language), PROM development and pilot studies, content validity (relevance, comprehensiveness, comprehensibility), and remaining measurement properties (structural validity, internal consistency, cross-cultural validity, reliability, measurement error, criterion validity, construct validity, and responsiveness). Quality of evidence was assigned for each measurement property of included PROMs. An overall recommendation level was assigned based on content validity and quality of the evidence of measurement properties. Results We identified 54 acne PROM development or validation studies for 10 acne-specific PROMs, 6 dermatology-specific PROMs, and 5 generic PROMs. Few PROMs had studies for responsiveness. The only acne-specific PROMs with sufficient evidence for content validity were the CompAQ and Acne-Q. Based on available evidence, the Acne-Q and CompAQ can be recommended for use in acne clinical studies. Conclusions and Relevance Two PROMs can currently be recommended for use in acne clinical studies: the Acne-Q and CompAQ. Evidence on content validity and other measurement properties were lacking for all PROMs; further research investigating the quality of remaining acne-specific, dermatology-specific, and generic HRQoL PROMs is required to recommend their use.
Clonal haematopoiesis is associated with higher mortality in patients with cardiogenic shock
Authors: Fernando L. Scolari, Sagi Abelson, Darshan H. Brahmbhatt, Jessie J.F. Medeiros, Chun‐Po S. Fan, Nicole L. Fung, Vesna Mihajlovic, Markus S. Anker, Madison Otsuki, Patrick R. Lawler, Heather J. Ross, Adriana C. Luk, Stefan Anker, John E. Dick, Filio Billia
Journal: European Journal of Heart Failure (2022)
Subclinical Leaflet Thrombosis and Anticoagulation After Transcatheter Aortic Valve Replacement
Authors: Thomas J. Cahill, Ajay J. Kirtane, Martin Leon, Susheel K. Kodali
Journal: JAMA Cardiology (2022)

Subclinical leaflet thrombosis affects approximately 15% of patients after transcatheter aortic valve replacement (TAVR). The pathophysiology and clinical significance of leaflet thrombosis remain incompletely understood. Defining the optimal management strategy in patients who are asymptomatic, including the role for oral anticoagulation (OAC), is a key challenge for the field.Three recent randomized trials have evaluated the role of OAC in patients after TAVR. These studies have confirmed prior observational data suggesting that OAC is effective at prevention of subclinical leaflet thrombosis. Overall, however, OAC does not lead to a clinical benefit over the period studied, and in some patients may be harmful owing to bleeding risk.Strategies for identification of patients in whom the benefit of OAC outweighs the risks are required for optimization of long-term outcome after TAVR. This requires clearer insights into the mechanisms of asymptomatic leaflet thrombosis, its clinical significance, and patient-specific risks of bleeding and structural valve degeneration.
Targeting of Nrf2 improves antitumoral responses by human NK cells, TIL and CAR T cells during oxidative stress
Authors: Stefanie Renken, Takahiro Nakajima, Isabelle Magalhaes, Jonas Mattsson, Andreas Lundqvist, Elias S J Arnér, Rolf Kiessling, Stina Linnea Wickström
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Adoptive cell therapy using cytotoxic lymphocytes is an efficient immunotherapy against solid and hematological cancers. However, elevated levels of reactive oxygen species (ROS) in the hostile tumor microenvironment can impair NK cell and T cell function. Auranofin, a gold (I)-containing phosphine compound, is a strong activator of the transcription factor Nrf2. Nrf2 controls a wide range of downstream targets important for the cells to obtain increased resistance to ROS. In this study, we present a strategy using auranofin to render human cytotoxic lymphocytes resistant toward oxidative stress. Methods Melanoma patient-derived tumor infiltrating lymphocytes (TIL) and healthy donor-derived NK cells and CD19-directed CAR T cells were pretreated with a low dose of auranofin. Their resistance toward oxidative stress was assessed by measuring antitumoral responses (killing-assay, degranulation/CD107a, cytokine production) and intracellular ROS levels (flow cytometry) in conditions of oxidative stress. To confirm that the effects were Nrf2 dependent, the transcription level of Nrf2-driven target genes was analyzed by qPCR. Results Pretreatment of human TIL and NK cells ex vivo with a low-dose auranofin significantly lowered their accumulation of intracellular ROS and preserved their antitumoral activity despite high H 2 O 2 levels or monocyte-derived ROS. Furthermore, auranofin pretreatment of CD19 CAR-T cells or TIL increased their elimination of CD19 +tumor cells or autologous tumor spheroids, respectively, especially during ROS exposure. Analysis of Nrf2-driven target genes revealed that the increased resistance against ROS was Nrf2 dependent. Conclusion These novel findings suggest that Nrf2 activation in human cytotoxic lymphocytes could be used to enhance the efficacy of adoptive cell therapy.
P1031: LOW-DOSE DOACS IN VERY HIGH-RISK MYELOPROLIFERATIVE NEOPLASMS: LESS BLEEDING BUT MORE ARTERIAL THROMBOTIC EVENTS
Authors: L. Herbreteau, L. Papageorgiou, L. Le Clech, G. Garcia, C. James, B. Pan-Petesch, F. Couturaud, E. Lippert, G. Gerotziafas, J.-C. Ianotto
Journal: HemaSphere (2022)

Background: Direct oral anticoagulants (DOACs) have recently proven their efficacy and safety, as primary and secondary prevention agents, for thrombosis in cancer patients. Thrombotic and haemorrhagic events are major causes of morbidity and mortality in Philadelphia-negative myeloproliferative neoplasm (MPN) patients. However, the best agent to prevent thrombotic events without increasing the bleeding incidence among these patients remains uncertain. Aims: In this study, we aimed to determine if DOACs might be an interesting choice to reduce the thrombotic risk in high-risk MPN patients. Methods: We analysed a large multicentric cohort of MPN patients treated with DOACs for atrial fibrillation (AF) or thrombotic events. We evaluated the overall thrombosis and haemorrhage rates related to DOACs, and also by the DOAC type (apixaban or rivaroxaban) as well as the daily dosage prescribed. Results: We included 135 MPN patients with a median follow-up of 23.8 months since DOAC initiation. Twenty patients (14.8%) developed 30 thrombotic events (28 arterial thromboses in 19 patients) for a global incidence of 6.5% patient-years. No difference was highlighted between apixaban and rivaroxaban in terms of thrombosis risk, but the incidence of arterial thrombosis was significantly higher on low-dose DOACs (11.9 vs. 4.5% patient-years, p=0.04). Bleeding events were more frequent in the full-dose group (15.2 vs. 41.2%, p=0.006). However, major and clinically relevant non major (CRNM) bleeding events occurred in 18 patients (13.3%), with no difference between the DOAC types or the DOAC doses. In multivariate analysis, age was the only identified thrombotic risk factor, whereas risk factors for major or CRNM bleeding were a full-dose treatment regimen and a combination of DOAC and low-dose aspirin. Image:Summary/Conclusion: DOACs seem effective in preventing venous thrombosis in MPN patients with AF or thrombotic events. For these high-risk patients, low-dose DOACs exposed patients to more arterial thrombosis but fewer bleeding events. Prospective studies are now needed to evaluate and compare DOACs to the currently recommended antithrombotic drugs for high-risk MPN patients.
P1431: MOLECULAR CHARACTERIZATION AND LENTIVIRAL CORRECTION OF IN VITRO ERYTHROPOIEIS IN PATIENTS WITH A NOVEL RECESSIVE CONGENITAL DYSERYTHROPOIETIC ANEMIA TYPE III (CDA TYPE IIIB).
Authors: G. Hernández, L. Romero-Cortadellas, X. Ferrer-Cortès, V. Venturi, M. Dessy-Rodriguez, M. Olivella, A. Husami, C. Pérez de Soto, R. M. Morales-Camacho, A. Villegas, F.-A. González-Fernández, M. Morado, T. A. Kalfa, O. Quintana-Bustamante, S. Pérez-Montero, C. Tornador, J.-C. Segovia, M. Sánchez
Journal: HemaSphere (2022)

Background: Congenital dyserythropoietic anemia type III (CDA III) is one of the rarest types of CDA. The autosomal dominant form of CDA III, originally described as familial erythroid multinuclearity and so far identified in two families, is due to a monoallelic missense mutation in the KIF23 gene. We previously identified three different families affected with a recessive form of CDA III with missense mutations in the RACGAP1 gene, the partner of KIF23. Aims: To further characterize the erythropoyesis of these patients and to perform lentiviral transduction of the WT gene to observe the rescue of the phenotype observed in the patients (multinucleation, macrocytosis...). Methods: We have isolated CD34+ cells from peripheral from two of the patients and performed an in vitro erythroid differentiation. For the characterization of the differentiation process we have used flow cytometry to differentiate the pupulations of differentiating erythroid cells by immunostaining. By cytospin preparations we have studied the multinucleation, enucleation and size of the cells. Results: Cells from patients showed a marked growth impairment compared with healthy donors. Cells at day 9 and 14 of the differentiation process show a high percentage of multinucleation with more than 2 nuclei, nuclear deformities and mitotic problems. At the final stage of erythroid differentiation, in the patient-derived cultures we observe a decrease in the production of erythrocytes, and the ones that are being produced show a clear macrocytic phenotype. The observed multinucleation and macrocytosis observed in the in vitro differentiation is in line with the observation in the bone marrow and peripheral blood from the patients, indicating that we can successfully recapitulate in vitro the erythropoiesis process from the patients. Additionally, flow-cytometry assessment of the erythroid differentiation shows a delay in the process where we observe an increased presence of erythroid progenitors (CD71+ only) at later stages and a reduced erythroid (CD235a+ only) production. Importantly, lentiviral transduction of the WT RACGAP1 gene in vitro could rescue the defects in erythroblast growth, multinucleation, macrocytosis, and enucleation. Summary/Conclusion: These results supports that mutations in the RACGAP1 gene are the genetic origin of the CDA IIIb disease.
P676: LOW-DOSE FCR COMPARED TO BR IN PREVIOUSLY UNTREATED PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA WITHOUT TP53 ABERRATIONS: A REAL – WORLD RETROSPECTIVE ANALYSIS BY THE CZECH CLL STUDY GROUP.
Authors: L. Smolej, Y. Brychtová, E. Cmunt, M. Oršulová, P. Vodárek, M. Dostál, P. Turcsányi, R. Urbanová, A. Panovská, J. Zuchnická, J. Mihályová, D. Lysák, M. Brejcha, H. Móciková, K. Klásková, M. Šimkovič, M. Špaček, M. Doubek
Journal: HemaSphere (2022)

Background: Low – dose fludarabine, cyclophosphamide, and rituximab (LDFCR) regimen showed promising activity in treatment-naïve elderly / comorbid patients (pts) with chronic lymphocytic leukemia (CLL) (Smolej et al., Br J Haematol. 2021). However, no data are available regarding comparison to bendamustine and rituximab (BR), which has been one of the predominant first - line options for CLL patients ineligible for full – dose FCR. Aims: To perform a historical comparison of the efficacy and safety of LDFCR and BR regimens used as the first - line therapy of CLL within routine practice. Patients with 17p deletion and/or TP53 mutation were not included in this analysis because chemoimmunotherapy is no longer indicated in this extremely unfavourable subgroup due to very low activity. Methods: The analysis included 237 pts treated with LDFCR and 320 pts treated with BR (median age, 69 vs 70 years; males, 70 vs 61%; median CIRS score, 6 vs 7; Rai stage III/IV, 57 vs 59%; bulky lymphadenopathy > 5cm, 35 vs 35%; unmutated IGHV, 74 vs 70%, deletion 11q, 28 vs 26%) treated between March 2009 and December 2019 at 17 centers cooperating within the Czech CLL Study Group. LDFCR consisted of fludarabine 20 mg/m2 orally or 12 mg/m2 on days 1-3, cyclophosphamide 150mg/m2 orally or iv on days 1-3, and rituximab 500 mg/m2 D1 (375 mg/m2 in Cycle 1). BR included bendamustine 90 mg/m2 iv on days 1-2 and rituximab 500 mg/m2 D1 (375 mg/m2 in Cycle 1). Median follow – up was 98 months for LDFCR and 57 months for BR. Results: Distribution of demographic data and prognostic factors was comparable between LDFCR and BR groups. The overall response rate / complete remissions were similar for LDFCR vs BR (84/46% vs. 88/51%, p=n.s.). The median progression – free survival (PFS) was 30 vs 34 months (hazard radio [HR] 0.90; p=n.s.); PFS was markedly longer in pts with mutated IGHV and absence of del 11q (LDFCR vs BR, median 58 vs 59 months, HR 0.84; p=n.s.; Fig. 1a). Median overall survival (OS) was 73 vs 77 months for LDFCR vs BR (HR 1.09; p=n.s.) but markedly longer (median 116 months vs not reached) in patients with mutated IGHV without del 11q (HR 0.90; p=n.s.; Fig. 1b). Grade ≥ 3 neutropenia occurred in 55% (LDFCR) vs 51% (BR) pts but serious infections developed in 15% vs 20% pts only. Image:Summary/Conclusion: Our data indicate that both low-dose FCR and BR are well – tolerated regimens with similar efficacy and safety and represent a suitable first - line treatment alternative for elderly / comorbid CLL patients with favourable biological prognosis. Detailed results including multivariate analysis will be presented.
P727: NK-CELL IMMUNOEDITING BY MESENCHYMAL STROMAL CELLS IN MDS
Authors: V. Bisio, B. Schell, L.-P. Zhao, E. Lereclus, M. Boy, A. Bonaud, A. Caignard, A. Toubert, P. Fenaux, M. Espéli, K. Balabanian, L. Adès, N. Dulphy
Journal: HemaSphere (2022)

Background: Disorders of the immune system contribute to the pathophysiology and progression of myelodysplastic syndrome (MDS). Cytotoxic Natural Killer (NK) lymphocytes have been extensively studied for their anti-leukemic activity. However, whether the dysplastic bone marrow (BM) in MDS can directly imprint NK cells and hence alter immunosurveillance is still controversial. Extensive characterizations of MDS patients uncovered deep perturbations in the phenotype and function of cytotoxic lymphocyte subsets and of the stromal compartment, in particular mesenchymal stromal cells (MSC), linked with disease predisposition, initiation and progression. However, few studies have been undertaken to characterize the interactions established within the MDS immune microenvironment between immune and stromal cells. Aims: Recent studies on MDS BM ecosystem suggest a possible symbiotic relationship between cancer, immune and stromal cells. Our project thus aims to underpin the influence of the pathological MSC from MDS BM over NK cells to create a leukemia-permissive microenvironment allowing disease development and progression. Methods: We performed an extensive in vitro characterization of the NK and MSC interactions by co-culture system. Healthy donor (HD) NK cells were co-cultured either with MSC isolated from HD or MDS patient BM samples and were analyzed by high-parametric flow-cytometry, qRT-PCR, secretome and imaging assays. Results: Analyses of supernatants from MSC/NK co-cultures unveiled altered secretion of soluble factors related to inflammation and BM homing such as IL6, CCL2 and CXCL10 in the pathologic condition compared to the healthy one. MDS MSC did not support efficiently NK-cell viability. Moreover, NK cells cultured with MDS MSC were less efficient at eliminating cancer cells compared to NK cells cultured with HD MSC. Finally, metabolic analyses uncovered an altered NK cell energetic profile dictated by the different MSC that could contribute to their poor survival and reduced cytolytic function. Summary/Conclusion: Altogether, our results suggest that MSC from MDS BM edit NK cells to promote an immunosuppressive environment facilitating MDS escape and progression. Further analyses are ongoing to underpin the pivotal role of immune-microenvironment interactions in the treatment response. We expect this study to identify new biomarkers to forecast disease progression and open an avenue for new combination therapies targeting the tumour microenvironment.
P694: INVESTIGATING THE ROLE OF CELL ADHESION MOLECULES IN TUNNELING NANOTUBES FORMATION IN CHRONIC MYELOID LEUKEMIA MICROENVIRONMENT
Authors: L. Turos-Korgul, A. Zieminska, L. Parker, K. Piwocka
Journal: HemaSphere (2022)

Background: The cross-talk and interactions between leukemia cells and their microenvironment play an important role in the development of drug resistance. Tunneling nanotubes (TNTs) represent a novel type of direct cell-cell communication way allowing for direct transfer of different types of cargo between distant cells. Our previous studies (Kolba et al., 2019) have shown that these structures are formed between bone marrow stromal HS-5 cells and chronic myeloid leukemia (CML) K562 cells. Significantly, TNT-mediated transfer of membrane vesicles from stromal to leukemic cells resulted in the stroma-mediated protection of CML cells from imatinib-induced apoptosis. Despite the efforts made to understand the molecular mechanisms regulating TNTs formation, they still remain unclear - especially in the leukemia microenvironment. We have shown that TNTs are formed between stromal and leukemic cells, following direct cell-cell interaction and cell dislodgement. Thus, we have focused our attention on cell adhesion molecules, as potential key players in tunneling nanotubes formation and TNT-mediated vesicles transfer between leukemic and stromal cells. Aims: The aim of presented studies was to elucidate the role of CD44 and ITGβ1 - one of the most important cell adhesion molecules, in TNTs formation between leukemic and stromal cells and TNT-mediated exchange of vesicles. Methods: To examine this, we established the HS-5 stromal cell line with silenced CD44 protein expression. Then, we co-cultured control (wt) or CD44-silenced HS-5 cells with leukemic K562 cells. For ITGβ1 studies, we used blocking anti-ITGβ1 antibody. Using confocal microscopy, three types of TNTs in co-cultures were counted: homotypic TNTs formed between stromal cells, homotypic TNTs formed between CML cells and TNTs formed between stromal and CML cells (heterotypic). Moreover, the TNT-mediated transfer of cellular vesicles from stromal to leukemic cells was assessed in these co-cultures using flow cytometry. Since CD44 expression increases in CML cells after co-culture with stroma, we examined its potential role in the drug resistance in CML acceptor cells. To do this, rhodamine-123 efflux assay was used. Results: We found that both, tunneling nanotubes number and uptake of cellular vesicles by leukemia, decreased after co-culture with CD44-silenced stromal cells and after blocking with anti-ITGβ1 antibody. Flow cytometry analyses of rhodamine-123 efflux showed significantly increased efflux pump activity in leukemic acceptor cells. Summary/Conclusion: Our data suggest that CD44 and ITGβ1 can play an important role in formation of tunneling nanotubes between leukemic and stromal cells and TNT-mediated cellular vesicles exchange. Moreover, CD44 presented in acceptor cells is involved in the development of drug resistance in leukemic cells, by promoting activity of efflux transporters.